The long-term objective of this project is to define the immunological mechanisms that determine the outcome of dengue virus (DV) infection. A large body of information supports the model of immunopathogenesis of severe dengue disease;however, open questions remain about the principal determinants of disease. DV interaction with host innate and adaptive immunity responses is highly complex, and can result in the production of pro-inflammatory, antiinflammatory, and/or vasoactive cytokines. This Project seeks to understand the contribution of individual components of the immune response to different clinical disease manifestations. These findings will be important for vaccine development, by identifying the key immunologic correlates of vaccine-induced protection as opposed to immunopathology on subsequent exposure to DV. The Specific Aims of this Project are: 1. to define the viral and innate host determinants of the cellular response to DV infection, by determining the dendritic cell (DC) cytokine response to DV strains associated with different disease severity and the association of DC responses with host genotypes; 2. to define the immunological mechanisms contributing to clinical disease in acute DV infection, by determining the kinetics of activation and expansion of DV-specific B cells and T cells; 3. to define immunological correlates of the response to tetravalent DV immunization, by determining the associations between pre-existing DV-specific immunity and the response to vaccination and between the vaccine-induced DV-specific immunity and clinical outcome (adverse events, protection, and breakthrough DV infections). Dengue is an important tropical mosquito-borne viral disease that causes shock as a result of the body's immune response. We will study how different parts of the host immune system react to infection with dengue virus to understand how virus infection causes disease. This research will help guide the development of vaccines and new treatments for dengue.